Safety of unconventional antibody-drug conjugate L-DOS47 in a phase I/II monotherapy study targeting advanced NSCLC
Bibliographic record
Abstract
Introduction Tumor acidity is emerging as a hallmark of cancer and carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) expression is frequently increased in acidic tumors. L-DOS47, a novel antibody-drug conjugate (ADC), consists of jack bean urease cross-linked to anti-CEACAM6 nanobodies. L-DOS47 is thus both targeted to CEACAM6-expressing tumors and designed to improve tumor control by neutralizing the acidic tumor microenvironment (TME) through ammonia and bicarbonate production from local urea. Methods This open-label, non-randomized study evaluated safety and tolerability of L-DOS47 in Stage IIIB/IV non-small cell lung cancer (NSCLC) patients. The Phase I 3 + 3 dose escalation aimed to determine the maximum tolerated dose (MTD) of L-DOS47 administered once/week over 14 days followed by seven days rest. Phase II explored twice-weekly dosing. Results 55/90 patients enrolled in Phase I received L-DOS47 up to 13.55 μg/kg. Although one dose-limiting toxicity (DLT) occurred in a patient at 5.76 μg/kg, MTD was not reached. Common treatment-emergent adverse events (TEAEs), reported by 38% of patients, were respiratory/thoracic/mediastinal disorders including dyspnea. No complete (CR) or partial responses (PR) were observed in Phase I or Phase II, despite the latter’s intensified dosing regimen; however, Phase I post-hoc exploratory analyses found that progression-free survival (PFS) was significantly extended at doses ≥5.76 μg/kg (P=0.0203). Anti-L-DOS47 antibody (ADA) titers were not associated with AE or shorter PFS. Immunohistochemistry (IHC) screening of an unrelated cohort revealed high CEACAM6 expression in 45.2% NSCLC cases. Conclusions L-DOS47 monotherapy was well tolerated at doses up to 13.55 μg/kg. No CRs or PRs were observed but extended PFS was associated with higher doses. Screening for CEACAM6 expression may select patients who are more likely to derive benefit from L-DOS47. Clinical Trial Registration https://www.clinicaltrialsregister.eu/ctr-search/search ; EudraCT Identifier: 2010-020729-42 (May 6, 2010).
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".